Triple negative breast cancer (TNBC) is an aggressive form of breast cancer that lacks the estrogen, progesterone and HER2 receptors, and accounts for 15-20% of all breast cancers in the US. TNBC has higher rates of relapse and poorer outcomes than other forms of breast cancer and owing to the lack of targetable surface receptors, TNBC are resistant to hormonal and HER2-targeted therapies. The particularly aggressive features of TNBC may be due to the enrichment of cancer stem cells (CSC) that have the unique biological properties necessary for maintenance and spreading of the tumor and through asymmetric division, can differentiate into cancer cells that compose the tumor bulk (Magee et al., Cancer Cell 2012, 21(3):283-96). Due to their resistance to traditional radio- and chemo-therapies (Nagano et al., Oncogene 2013, 32(44):5191-8), CSC represent a reservoir for the relapse, metastatic evolution, and progression of the disease after treatment. Therefore, successful eradication of CSC represents a major barrier towards effective cancer treatments.
The ability of CSC to resist common cytotoxic therapies relies on different mechanisms, including improved detoxification ability. The cystine-glutamate antiporter protein xCT (SLC7A11) regulates cysteine intake, conversion to cysteine and subsequent glutathione synthesis, protecting cells against oxidative and chemical insults via the p38MAPK pathway (Chen et al., Oncogene 2009, 28(4):599-609; Guo et al., Cancer Lett. 2011, 312(1):55-61). xCT expression is highly restricted to a few normal cell types (neurons and a subset of macrophages) but elevated levels of xCT protein are observed in a high percentage of invasive mammary ductal tumors including TNBC (Lanzardo et al. Cancer Res. 2016, 76(1):62-72). High levels of xCT mRNA and protein correlate with significant reduction in distal metastases-free and overall survival (Briggs et al., Cell 2016, 166(1):126-39; Gyorffy et al., Breast Cancer Res Treat. 2010, 123(3):725-31). xCT expression is upregulated in breast CSC (BCSC) and other solid tumor stem cells, and several studies show that xCT physically interacts with the well-known stem cell marker, CD44 (Nagano et al., Oncogene 2013, 32(44):5191-8; Hasegawa et al., Oncotarget 2016, 7(11):11756-69; Ishimoto et al., Cancer Cell 2011, 19(3):387-400; Ju et al., Mechanisms and Therapeutic Implications. Theranostics 2016, 6(8):1160-75; Yoshikawa et al., Cancer Res. 2013, 73(6):1855-66). The frequency of xCT expression on a variety of CSC suggests that therapies targeting xCT may be effective for a variety of tumors with high stem cell frequencies including gastrointestinal and pancreatic cancers.
A direct role for xCT in breast cancer metastasis was shown by inhibiting xCT function with the small molecule sulfasalazine (SASP), which resulted in significant decreases in metastatic foci in animal models and reductions in the frequency of CSC (Nagano et al., Oncogene 2013, 32(44):5191-8; Chen et al., Oncogene 2009, 28(4):599-609; Guan et al., Cancer Chemother Pharmacol. 2009, 64(3):463-72; Timmerman et al., Cancer Cell 2013, 24(4):450-65). However, SASP is labile and insoluble under physiological conditions, has vast off-target effects, low bioavailability and requires high doses to inhibit xCT in vivo (Timmerman et al., Cancer Cell 2013, 24(4):450-65; Shitara et al., Gastric Cancer 2016; Linares et al., Expert Opin Drug Saf 2011, 10(2):253-63; Robe et al., BMC Cancer 2009, 9:372). Therefore, new therapeutic modalities specifically targeting xCT need to be developed for clinical use.